1. Field of the Invention
This invention is directed to novel heteromacrocyclic compounds (herein sometimes referred to as lariat ethers) which, due to the incorporation of three features, i. e., macroring, sidearm and electron-deficient aromatic species, affords a cation with a three-dimensional array of binding sites. The invention is also directed to an electrochemical switching process utilizing said lariat ethers wherein they can be reversibly converted from a weaker to a stronger cation binder. Although electron transfer herein is shown only by an electrochemical method, reduction may also be accomplished by reaction with chemical reducing agents such as sodium or potassium metal.
Several features are essential to the present invention. These include a macrocyclic polyether ring capable of binding a cation such as sodium within it. Examples of macrocyclic rings known in the literature which can do so range from 12-60 members. A macrocyclic polyether ring capable of binding cations is a necessary, but not sufficient condition of the instant invention. A sidearm or tether of some sort is necessary to attach the aromatic residue to the macroring. This is also a necessary, but not sufficient condition. Finally, the aromatic residue must be sufficiently electron deficient that it can accept an electron and form a radical anion. Implicit in this is the notion that the electron attracting group or groups, which make the aromatic residue susceptible to reduction, must also be capable of interacting as donor groups with the ring-bound cation, thusly: ##STR1##
Any person skilled in the art can use this three-part concept and utilize the invention by conducting the following steps. First, a macroring would be chosen. According to our specification, the ring would contain from 12-36 atoms selected from the group C, N, O or S. Second, a decision would be made concerning the point of attachment to be used for the sidearm. Since the ring consists only of C, N, O and S, and since the latter two elements are normally divalent, and since both valences of a divalent species must be utilized to form a ring, either carbon or nitrogen would be chosen as the point of attachment (hereinafter referred to as the pivot atom) for each sidearm bearing an electron deficient residue. Third, a sidearm would be selected. According to our specification, the sidearm could contain a variety of atoms and arrangements thereof. The key consideration is that, when the aromatic residue is attached to the sidearm, the correct geometrical relationships of the present invention must apply. Obviously, the appropriateness of the relationship can only be determined after an electron deficient aromatic residue is selected. If the aromatic residue selected is, for example, 2-nitrophenyl, the sidearm can be shorter than if the residue selected is 3-nitrophenyl to utilize the instant invention. One could prepare a molecular model, have a computer graphics program plot a structure or use any other technique which would allow the appropriate length and geometric relationship of the sidearm to be determined. Any such determination would take account of known geometrical relationships and inherent molecular flexibilities in accord with the rules of conformational analysis well known to those skilled in this art.
2. Description of the Prior Art
"Lariat Ethers" having appropriately placed sidearms can, in many cases, enhance the binding between a ligand and cation as compared to the binding level observed for a simple, monocyclic system. See 1, (a) Gokel, G. W., Dishong, D. M., Diamond, C. J., J., Chem. Soc. Chem. Commun., 1980, 1053; (b) Dishong, D. M., Diamond, C. J., Gokel, G. W., Tetrahedron Letters, 1981, 1663; (c) Schultz, R. A., Dishong, D. M., Gokel, G. W., Tetrahedron Letters, 1981, 2623; and (d) Dishong, D. M., Diamond, C. J., Cinoman, M. I., Gokel, G. W., J. Am. Chem. Soc., 1983, 105, 586.
Binding strength has been altered in crown ethers and cryptand compounds by photoswitching. See 2. (a) Shinkai, S., Shigematsu, K., Kusano, Y., Manabe, O., J. Chem. Soc. Perkin Trans. I, 1981, 3279; (b) Shinkai, S., Minami, T., Kusano, Y., Manabe, O., Tetrahedron Letters, 1982, 2581; (c) Nakamura, H., Nishida, H., Takagi, M., Ueno, K., Bunseki Kagaku, 1982, 31, E131; (d) Shinkai, S., Ogawa, T., Kusano, Y., Manabe, O., Kibukawa, K., Goto, T., Masuda, T., J. Am. Chem. Soc., 1982, 104, 1960; (e) Shinkai, S., Minami, T., Kusano, Y., Manabe, O., J. Am. Chem. Soc., 1982, 104, 1967; and (f) Shinkai, S., Minami, T., Kouno, T., Kusano, Y., Manabe, O., Chemistry Lett., 1982, 499.
Ionization of acidic functions (both in the ring and on pendant groups) has also been used for this purpose. See 3. (a) Takahashi, M., Takamoto, S., Bull Chem. Soc. Jpn., 1977, 50, 3413; (b) Stetter, H., Frank, W., Angew. Chem. Int. Ed. Engl., 1976, 15, 686; (c) Desreux, J. F., Inorg. Chem., 1980, 19, 1319; (d) Stetter, H., Frank, W., Mertens, R., Tetrahedron, 1981, 37, 767; (e) Tazaki, M., Nita, K., Takagi, M., Ueno, K., Chemistry Lett., 1982, 571; (f) Nakamura, H., Nishida, H., Takagi, M., Ueno, K., Analytica Chim. Acta, 1982, 139, 219; (g) Charewicz, W. A., Bartsch, R. A., Analytical Chem., 1982, 54, 2300; and (h) Shinkai, S., Kinda, H., Araragi, Y., Manabe, O., Bull. Chem. Soc. Jpn., 1983, 56, 559.
Analogously, protonation of amines has been used to alter the binding strength. See 4. (a) Tsukube, H., Tetrahedron Letters, 1983, 24, 1519, and (b) Tsukube, H., J. Chem. Soc. Perkin Trans I, 1983, 29.
Compound 7, shown on page 19 of PCT WO No. 82/04253 shows a superficial resemblance to the claimed compounds. It is not related to the compounds claimed herein because, although it clearly bears a reducible pendant residue, no donor group in the sidearm is in a position to interact with a ring-bound cation. Both the azo linkage and the nitro group are in the para positions. The nitro group is especially remote and would remain so even if the azo linkage could somehow be isomerized from the stable trans ground state to the less stable cis form.
The compounds disclosed in U.S. Pat. No. 4,436,923 are macrocyclic polyether compounds containing pendant nitroaromatic residues. Since they are polysubstituted aromatic residues, even after the obvious deprotonation of the secondary amino group takes place during reduction, the nitroaromatic group could still undergo reduction. This is irrelevant, however, since the reducible aromatic residue is attached to a second aromatic residue which is integral to the macrocycle. The nitro groups could not reach farther than the aromatic ring to which they are attached and thus could not interact with a ring-bound cation when reduced. This is especially true in the reduced form when electron spin is distributed over the nitro groups making them flat.
In addition, the compounds fail to meet the specification of the instant application, said macrocyclic ring must have at least one pendant group attached to either carbon or nitrogen contained within the ring structure. The compounds of U.S. Pat. No. 4,436,923 are attached to a nitrogen atom further attached to an aromatic residue, the latter of which is part of the ring structure.
The compounds of general formula (1) shown in Japanese Pat. No. 57-4976 might seem to meet the specifications set forth in the claims of the instant patent. This is not true for two reasons. When an acidic proton and a protonatable amine are present in the same molecule, the inherent cation binding of the species is dramatically reduced. Although no homogeneous equilibrium cation binding data are available in the Japanese patent, information bearing directly on this particular case is available from some recent work of our own which may be found in Gatto, V. J., Gokel, G. W., J. Am. Chem. Soc. 1984, 106, 8240. Therein, potassium cation binding constants for N-(2-methoxybenzyl)-4,13-diaza-18-crown-6 and N-(2-hydroxybenzyl)-4,13-diaza-18-crown-6 are reported. In the hydroxy compound, which is the direct analog (without the nitro group) of the Japanese compound, the potassium cation binding constant (Ks, in methanol) is 389 (log Ks=2.59). The corresponding methoxy compound has a potassium cation binding constant also in anhydrous methanol solution of 87,000 (log Ks=4.94). This tremendous difference is due to intramolecular proton transfer from phenolic hydroxyl to tertiary nitrogen. Such a proton transfer is likely to be much more substantial when a nitro group is present in the phenol since nitro is such a strongly acidifying function. Indeed, the pKa values for phenol and para-nitrophenol are, respectively, 9.89 and 7.15. Note that the lower the pKa value, the greater the acidity. Converting the logarithmic values to equilibrium constants, the nitrophenol is more than 500 times more acidic than the unsubstituted phenol. This means that proton transfer will be 500 times more of a problem for the nitrophenol than for phenol.
The problem with respect to the instant invention is that, when proton transfer occurs as we have shown conclusively that it will with these phenols, a phenoxide anion is produced. The oxygen anion is strongly electron releasing which will substantially increase the redox potential of any attached aromatic ring. If the --OH group was replaced by --OCH.sub.3, the compound would be similar to ortho-nitronanisole and still reducible. According to the Hammett (sigma para) constants [Hammett, L. P.; Physical Organic Chemistry, second edition, McGraw Hill Book Co., 1970, pages 355-357], only amino and dimethylamino among common substituents are more electron releasing than --O.sup.-. The compounds reported by Ueno are designed to be deprotonated easily to give colored anions which will complex with calcium cation.
In U.S. Pat. No. 3,952,015, "X" contained within the macroring may be ". . . O or NH, N-alkanoyl, N-benzoyl wherein the benzene ring is optionally substituted with --NO.sub.2, --NH.sub.2 or --CH.sub.3 . . .". The N-alkanoyl residues are irrelevant to the instant application since they contain no readily reducible groups. The N-benzoyl group, when substituted by nitro, is reducible at an accessible potential. Note, however, that N-benzoyl must be attached to tne macroring through an --N--CO--Ar linkage. Such linkages are always planar having 20 kcal/mole of resonance energy in each amide bond. Indeed, the amide or peptide link is described by Stryer in his standard biochemistry text [Stryer, L., Biochemistry, W. H. Freeman and Co., Second Edition, 1981, p. 28] as a "rigid and planar" unit. This is, of course, a key feature in the structures of peptides. The compounds alluded to in U.S. Pat. No. 3,952,015 would not be relevant in any event if the nitro group was attached to the benzene ring in either the 3- or 4-position. When it is attached at the 2-position, (i. e., ortho, it is also irrelevant since the ring must be coplanar with the --N--CO-- link. Likewise, the nitro group will favor coplanarity with the aromatic ring, and the nitro group will be incapable of interacting with a ring-bound cation. Even if the adjacent --N--CO-- and --NO.sub.2 groups are distorted, the pendant aromatic ring cannot reach back over the macroring. Finally, crown compounds have been structurally altered by oxidative dimerization of attached sulfhydryl groups. See Minami, T., Shinkai, S., Manabe, O., Tetrahedron Lett., 1982, 5167. Like the other prior art discussed above, none incorporated all three features, i. e., macroring, sidearm and electron-deficient aromatic residue of the lariat ethers in the correct geometrical relationships of the present invention to produce a switching mechanism.
One object of the instant invention is to produce novel heteromacrocyclic compounds capable of offering a cation a three-dimensional array of donor groups. Another object is to produce heteromacrocyclic compounds which increase cation binding power when reduced. Still another object of the invention is to provide an electrochemical switching process utilizing said heteromacrocyclic compounds wherein they can be reversibly converted from a weaker to a stronger cation binder. Other objects will become apparent from a reading hereinafter.